New aspects of airway mechanics in pre- term infants M. Henschen*

Eur Respir J 2006; 27: 913–920
DOI: 10.1183/09031936.06.00036305
CopyrightßERS Journals Ltd 2006
New aspects of airway mechanics in preterm infants
M. Henschen*,#,", J. Stocks#, I. Brookes+ and U. Frey1
ABSTRACT: High-frequency respiratory impedance data measured noninvasively by the highspeed interrupter technique (HIT), particularly the first antiresonance frequency (far,1), is related
to airway wall mechanics.
The aim of this study was to evaluate the feasibility and repeatability of HIT in unsedated preterm infants, and to compare values of far,1 from 18 pre-term (post-conceptional age 32–37 weeks,
weight 1,730–2,910 g) and 18 full-term infants (42–47 weeks, 3,920–5,340 g).
Among the pre-term infants, there was good short-term repeatability of far,1 within a single sleep
epoch (mean (SD) coefficient of variance: 8 (1.7)%), but 95% limits of agreement for repeated
measures of far,1 after 3–8 h were relatively wide (-41 Hz; 37 Hz). far,1 was significantly lower in
pre-term infants (199 versus 257 Hz), indicating that wave propagation characteristics in pre-term
airways are different from those of full-term infants. The present authors suggest that this is
consistent with developmental differences in airway wall structure and compliance, including the
influence of the surrounding tissue.
Since flow limitation is determined by wave propagation velocity and airway cross-sectional
area, it was hypothesised that the physical ability of the airways to carry large flows is
fundamentally different in pre-term than in full-term infants.
KEYWORDS: Infant, interrupter technique, pre-term, respiratory function tests
here is a significant body of evidence from
epidemiological studies confirming a link
between childhood lower respiratory illness and wheezing and the development of adult
chronic respiratory disease [1–6]. The nature of
this link, the biological mechanisms which
mediate it, and the genetic, developmental and
environmental factors which influence its expression have been the focus of considerable research
effort in recent years. One concept evoked to
explain this association is that of ‘‘programming’’, the permanent alteration of the structure
and function of organs and tissues by factors
operating during sensitive periods in foetal or
early post-natal life [4]. Factors implicated in
programming of the respiratory system include
foetal nutrition [7], foetal exposure to maternal
smoking during pregnancy [8], pre-term delivery
and exposure to environmental allergen or viral
respiratory infections during infancy [3, 9]. Little
is known about the impact of pre-term delivery
on airway development, although it has been
shown that this may result in a relative increase
in the amount of bronchial smooth muscle and
number of goblet cells, particularly among those
who require mechanical ventilatory support [10].
Pre-term delivery, even in the absence of any
neonatal respiratory disease or ventilatory
support, may have an adverse effect on subsequent lung growth and development, which
persists and may even worsen throughout the
first years of life [11–15].
EUROPEAN RESPIRATORY JOURNAL
VOLUME 27 NUMBER 5
T
To evaluate the impact of pre-term delivery on
airway development, it is essential to understand
the effect of developmental structural differences
on airway function. While all conducting airway
generations are formed by 16 weeks’ gestation,
with a linear increase in airway diameter
between 22 weeks’ gestation and 8 months postnatal age, true alveoli do not begin to develop
until ,30 weeks’ gestation, with subsequent
rapid increase in number, size and complexity
during the first 3–4 yrs of life [10]. Different
growth patterns of the airways and parenchyma
(dysanaptic growth) during foetal and early postnatal life result in airways that are relatively large
in relation to lung volume at birth [16]. This has
been reflected by functional measurements which
indicate relatively low airway resistance [17] and
an increased expiratory rate constant (change in
flow divided by the change in volume between 50
and 75% of expired forced vital capacity) in early
life [18]. Nevertheless, young infants, particularly
those delivered prematurely, who are often born
early for some abnormal reason, are prone to
AFFILIATIONS
*Dept of Paediatrics and Adolescent
Medicine, University Hospital of
Freiburg, Freiburg, Germany.
#
Portex Respiratory Unit, Institute of
Child Health,
"
Neonatal Unit, Homerton University
Hospital, London, and
+
Dept of Child Health, University of
Leicester, Leicester, UK.
1
Paediatric Respiratory Medicine,
Dept of Paediatrics, University
Hospital of Bern, Inselspital, Bern,
Switzerland.
CORRESPONDENCE
M. Henschen
Schwarzwald-Baar Klinikum
Villingen-Schwenningen GmbH
Vöhrenbacher Straße 23
D-78050 Villingen-Schwenningen
Germany
Fax: 49 7721933599
E-mail: [email protected]
Received:
March 26 2005
Accepted after revision:
January 22 2006
SUPPORT STATEMENT
M. Henschen was supported by the
Deutsche Forschungsgemeinschaft
(Bonn, Germany). J. Stocks was
supported by Portex Ltd (Hythe, UK).
U. Frey was supported by a grant
from the Swiss National Science
Foundation 32-68025.02 (Bern,
Switzerland).
European Respiratory Journal
Print ISSN 0903-1936
Online ISSN 1399-3003
c
913
AIRWAY MECHANICS IN PRE-TERM INFANTS
M. HENSCHEN ET AL.
airway narrowing and closure during tidal breathing, and
have increased vulnerability to wheezing disorders. This
emphasises the complex structure–function relationships in
the developing lung, including the fact that expiratory flows
are related not only to airway dimensions, but also to the
compliance of the airway wall [19] and of the surrounding
parenchyma and chest wall [16]. It has been shown in an
animal model, that structural differences of immature airways
may result in a markedly increased airway wall compliance
[20]. In addition, developmental changes in the properties of
the lung parenchyma [21, 22], dynamic control of endexpiratory lung volume [23], high chest wall compliance [24]
and diminished airway–tissue coupling [25] influence elastic
recoil of the respiratory system with subsequent impact on
functional airway diameter and airway wall mechanics. Due to
the complexity of these interactions, it is extremely difficult to
assess the potential impact of altered airway wall mechanics on
measured values of resistance or forced expiratory flows in
pre-term infants during the first months of life.
In 1998, the high-speed interrupter technique (HIT) was
proposed as a novel method to measure high frequency
respiratory impedance in vivo [26]. As explained later (see the
discussion section), it has been shown in both adults and
infants, that high frequency respiratory impedance data,
particularly the frequency at which the first antiresonance
(far,1) occurs, is influenced by the wave propagation velocity (n)
of pressure waves (i.e. wave speed) within the airways and is
related to airway wall mechanics [26–28]. In pre-term infants,
particularly during respiratory distress when higher intrathoracic pressures occur, airway wall mechanics will become
increasingly important for flow limitation. To better understand flow limitation, and thus wave propagation and airway
wall properties in pre-term infants, the aims of this study were:
1) to evaluate the feasibility and repeatability of applying the
HIT in unsedated pre-term infants, and 2) to assess developmental changes in airway wall mechanics by comparing values
of far,1 in healthy pre- and full-term infants.
MATERIALS AND METHODS
The present study was performed in two stages. In the first
stage, the feasibility and within-subject variability of using the
HIT to measure high frequency impedance (Z(f)) between 32
and 512 Hz were analysed in a group of healthy pre-term
infants, focusing particularly on the far,1, which is mainly
determined by wave propagation properties of pressure waves
in the airways (see discussion). During the second stage, values
of far,1 from this group of pre-term infants were compared with
those from healthy full-term infants measured under the same
conditions.
Subjects
Pre-term infants from the Neonatal Unit at the Homerton
University Hospital, London, UK, were eligible for recruitment
if they were born at f36 completed weeks of gestation without
major congenital abnormalities and required minimal ventilatory assistance (defined as continuous positive airway pressure
(CPAP) and/or supplemental oxygen for ,24 h after delivery).
Gestational age was assessed from mothers’ date of last
menstrual period and from obstetric ultrasound scans
performed at or before 20 weeks of pregnancy. The pre-term
914
VOLUME 27 NUMBER 5
infants were compared with a group of healthy full-term
infants recruited antenatally at the Dept of Paediatrics,
University Hospital of Berne, Switzerland. Infants were
ineligible for recruitment if they had experienced any
respiratory problems, including upper or lower respiratory
illnesses prior to testing. The study was approved by the
University of Berne, Berne, Switzerland and the East London
and City Research Ethics Committees, London, UK. Informed
written consent was obtained from the parents, who were
usually present during the measurements.
Study design
All infants were studied unsedated in natural sleep, 30 min to
1 h after a feed. In both centres, infants were measured using
an identical protocol and equipment [26, 29]. Respiratory data
were collected during consecutive periods of relatively quiet
regular breathing in room air, with the infant settled in the
supine position, while heart rate and oxygen saturation were
monitored. Impedance measurements were performed prior to
any other lung function measurements. A transparent Rendell–
Baker face mask (size 0; Ambu International, Bath, UK) was
held over the infant’s mouth and nose. A leak-free seal and
reduction of dead space was created using therapeutic silicone
putty (Carters, Bridgend, UK). The effective dead space
volume of the face mask was ,6 mL, as described previously
[30], while that of the tube with the propeller valve was 7 mL.
Between the short sets of measurements, the tube was
detached to minimise dead space and CO2 rebreathing.
Measurements were repeated 10–25 times within each test
occasion, provided the child remained undisturbed. Where
possible the entire protocol was repeated on the same day after
an interval of 3–8 h to assess repeatability of measurements.
High frequency impedance measurements Z(f)
The principles and technical details of the HIT have been
described in detail previously [29]. Identical custom-built
equipment was used in both centres. Briefly, high-frequency
respiratory input impedance was measured with a propeller
valve that rapidly (within 1 ms) occluded the airway opening
five times within a period of 0.15 s (duration of each period of
closure and opening being 15.5 ms) during tidal breathing
without disturbing the infant. The resulting pressure and flow
oscillations were measured by the wave tube technique [31]
using two piezo-electric transducers (EuroSensor; Model 33,
London, UK). Spectral analysis was used to calculate respiratory input impedance from the pressure and flow signals [32].
The far,1, defined by a zero crossing in the imaginary part in the
presence of a relative maximum in the real part of the
impedance spectrum (Zre(far,1)) was extracted from the
impedance spectrum, assessed between 32 and 512 Hz
(fig. 1). Data were not accepted for analysis if: 1) multiple
peaks occurred; 2) the relative maximum of Zre did not occur at
the zero-crossing in the imaginary part; 3) the coherence was
,0.9; or 4) oscillatory pressures changes were ,0.15 kPa [26].
After separate primary analysis at each centre (M. Henschen in
London, UK; I. Brookes in Bern, Switzerland), all data were
reviewed by the same person for acceptability (U. Frey,
Bern, Switzerland). Within each test occasion, the first 10
technically acceptable manoeuvres were taken for further
analysis.
EUROPEAN RESPIRATORY JOURNAL
M. HENSCHEN ET AL.
AIRWAY MECHANICS IN PRE-TERM INFANTS
Among the healthy full-term infants, 24 data sets with
technically acceptable coherence were obtained initially.
However, in six of these infants, the impedance spectra did
not show a consistent single first antiresonance but a multiple
peak resonance pattern. These data were excluded from
further analysis, because a dominant peak could not be
determined (see discussion).
12
10
Zin kPa·L-1·s-1
8
6
4
n
n n
nn
n
n n nn
n
n n
n
nn
nnn
n
n
nn
nn
n
n nn
n
n
n
n
n
ar,1
n
n n n
n
n
f
llll
l
l
lll
l
ll
ll
l
2
0
-2
n
l
lll
l
-6
l
ll
l
l l
ll
l
l
-8
FIGURE 1.
nn
Real part
n
nnnn nnnn nn n
nn
l
l
-4
100
n n n
n
200
ll
ll
l
ll l
300
400
Frequency Hz
ll
l
l
ll
llllll
llll
Imaginary part
500
600
Example of one measurement of a high-frequency impedance
spectrum from a single infant. The antiresonant frequency (far,1) is defined by the
relative maximum in the real part (Zin,re(far,1)) in the presence of a zero crossing in
The SD of repeat measurements of far,1 on a single test occasion
was ,30 Hz in all but three infants (maximum 55 Hz), and
was similar in pre-term and full-term infants (mean¡SD: 16¡3
and 23¡13 Hz, respectively). While this was relatively
independent of the absolute values, it equated to a mean CV
of 8 and 10% in each of the two groups, respectively.
Technically acceptable repeated measurements on two occasions were obtained after an interval (mean¡SD) of 5.4¡1.7 h
in eight of the pre-term infants. Within-occasion variability
during the second set of recordings was virtually identical to
that observed in the initial set of measurements. There was
minimal bias between repeated measures (the mean far,1 on the
first and second test occasions were 210 and 208 Hz,
respectively). However, the 95% limit of agreement for
individual subjects were relatively wide: -41–37 Hz.
the imaginary part. Zin: respiratory input impedance.
Statistics
Short-term repeatability of 10 technically acceptable measurements of far,1 within each test occasion was expressed as the
coefficient of variation (CV %51006SD/mean). BLAND and
ALTMAN [33] analysis was used to assess within-subject
between-occasion repeatability on the same day. Comparison
of results between pre-term infants and healthy fullterm infants were undertaken using the Wilcoxon two-sample
test.
RESULTS
Measurements of high-frequency input impedance during
tidal breathing were attempted in 21 healthy pre-term infants.
None of the infants woke up during the short measurement
period (range 4–15; median 6 min), but a sufficient number of
technically acceptable measurements could be obtained in only
18 infants. The mean¡SD number of attempted measurements
was 18¡3 and that of technically acceptable measurements
17¡4.
TABLE 1
Details of the remaining 18 pre-term infants together with
those of the 18 full-term infants are summarised in table 1. As
expected, the pre-term infants were younger, lighter and
shorter than those born full-term. A relatively high proportion
of males were studied, but there was no difference in sex
distribution between the groups. The proportion of babies in
whom both parents were northern European white people
was, however, considerably lower among the London pre-term
group than the Swiss full-term group (p,0.001). In the preterm infants one infant received CPAP therapy (20 h,
far,15157 Hz), while two had brief supplemental oxygen
(1 day, far,15195 Hz and 11 h, far,15177 Hz, respectively).
far,1 was significantly lower in pre-term than in full-term
infants (mean (95% confidence interval)) difference, pre-term–
full-term: -58 (-28– -88) Hz). On inspection of the data, there
was overlap according to both sex and ethnic group (data not
shown), although formal statistical comparison was precluded
by the small sample size.
Details of infants included in the study
Pre-term infants
Full-term infants
n
18
18
Male %
72
78
0.7
Both parents white northern Europeans %
17
100
,0.001
2.01¡0.35
3.55¡0.35
,0.001
34¡2
40¡1
,0.001
7 (4.5–10)
34 (29–38)
,0.001
35¡1
45¡1
,0.001
Birth weight kg
Gestational age weeks
Post-natal age days#
Post-conceptional age weeks
p-value
Test weight kg
2.12¡0.26
4.55¡0.43
,0.001
Crown–heel length cm
43.6¡2.2
55.7¡2.1
,0.001
far,1 Hz
199¡24
257¡60
,0.001
c
Data are presented as mean (SD), unless otherwise indicated. #: data presented as median (interquartile range). far,1: first antiresonance frequency.
EUROPEAN RESPIRATORY JOURNAL
VOLUME 27 NUMBER 5
915
AIRWAY MECHANICS IN PRE-TERM INFANTS
M. HENSCHEN ET AL.
DISCUSSION
The results of the present study show that it is feasible to apply
the HIT to pre-term infants in unsedated sleep and that values
of far,1 were significantly lower among apparently healthy preterm infants than their full-term counterparts. Once the infants
were spontaneously sleeping, antiresonant frequencies could
be detected in all unsedated infants without disturbance
during a short measurement period of 4–15 min. There was a
low failure rate, with only three pre-term infants showing ,10
technically acceptable manoeuvres. The short-term variability
of the first antiresonance within a single sleep epoch was very
acceptable and comparable with previous studies from healthy
full-term infants between 6–24 months of age [26, 30].
However, while there was no systematic group difference
between the two sets of measurements of far,1 on the same day
in the eight pre-term infants in whom this could be measured,
there was marked within-subject variability between results
collected after an interval of 3–8 h.
Interpretation of the findings and model hypothesis
Investigation of factors determining airway function in
immature infants is essential to further improve understanding
of the impact of pre-term delivery on the subsequent
development of airway structure and function. From a
structural point of view, airways are relatively large in relation
to lung volume during early life, but the maximal flows that
can be conveyed through such airways may be somewhat less
than anticipated, since such flows are a function of the n of
travelling pressures waves; hence, they are related not only to
diameter, but also to airway wall compliance [19]. One
hypothesis is that the structural immaturity of the airway
walls results in highly compliant airways, crucially determining flow limitation in immature airways of prematurely born
infants. The high compliance of the airway walls in immature
animals has been demonstrated in vitro [22, 34], but the
situation might be different in vivo and/or in human infants,
depending on the strength of airway–parenchyma attachments
and the relationship between lung and chest wall compliance
[24]. This relationship will be further complicated by the
tendency of young infants to dynamically elevate their endexpiratory volume, thereby further regulating airway patency
and elastic recoil, and by changes in sleep state, which may
affect both lung volume and upper airway tone [16, 23]. A true
picture of the role of these complex interacting structural and
functional systems can therefore only be estimated in vivo.
Since increased transmural pressures may affect airway
compliance [20, 35], infants who had received mechanical
ventilation were excluded from this study. Only one infant
received CPAP therapy (20 h; far,15157 Hz), while two had
brief supplemental oxygen (1 day, far,15195 Hz and 11 h,
far,15177 Hz). Visual inspection of results indicated no bias
with respect to data from these three infants, and identical
conclusions were reached, whether or not they were excluded
from the analysis.
The interpretation of these results in terms of their physiological meaning must be very cautious and can only be
undertaken by reference to simplified models. At higher
frequencies, pressure waves follow the physical laws of
acoustics. In a large-diameter, simple, rigid straight tube, n
corresponds to the first harmonic acoustic antiresonant
916
VOLUME 27 NUMBER 5
frequency, comparable to the sound pitch of a flute. The
frequency of this resonating sound is dependent on wave
speed, which in turn is mainly dependent on gas density and
the length of the tube. In a branching network of compliant
small tubes (such as the airways), the frequency at which this
antiresonance occurs is still dependent on n but, in such a
system, n does not correspond to the free field sound wave
speed, i.e. the wave speed in a simple, rigid straight tube.
Under such circumstances, n is no longer dependent simply on
length and gas density, but also on the airway wall mechanics
(compliance) and, to a minor extent, by airway diameter in
very small tubes. In the terminal airways of human adults
where the diameter is ,1 mm, n is 62% of the free-field speed
of sound [28]. Thus, in very peripheral airways, n is
significantly reduced. A reduction in n in these distal airways
would cause them to resonate at a lower frequency. More
important, however, is the influence of airway wall compliance. Airway wall compliance strongly influences n and, thus,
far,1 in compliant airways. The relationship between airway
path length, diameter, wall compliance, n and far,1 is highly
complex and the influence of their components cannot easily
be distinguished. Nevertheless, speculation is possible, based
on the theory of simplified elastic tube models and animal
models [36, 37].
A significantly reduced far,1 was found among the pre-term
group, who were not only more immature, but also younger
and smaller than the full-term infants. Since mean airway path
length must be shorter the smaller the infant, one might have
expected far,1 to be higher in this group. Indeed, assuming a
certain proportionality between crown–heel length and mean
airway path length [10], the mean airway path length would be
expected to be ,30% lower and, thus, far,1 to be ,30% higher
in the pre-term group. Theoretically, airway diameter also has
a certain influence on wave propagation in small tubes and,
therefore, far,1. However, based on published animal model
estimations [36, 37], and assuming that airway resistance was
,30% higher in pre-term than in full-term infants [17], a
corresponding diameter scaling factor would only decrease
far,1 by ,10% [36]. Based purely on length and diameter, far,1
would therefore be expected to be higher in younger, smaller
infants. This suggests that increased airway wall compliance
due to immaturity must have a significant influence on far,1
and hence n in pre-term infants. The latter would be consistent
with structural findings [22, 34].
Even though the impact of the different components on far,1
cannot be separated quantitatively, it can still be concluded
that differences in far,1 probably reflect differences in n in the
airways of pre-term compared with full-term infants. This has
crucial implications. Maximal flows through a compliant tube
are related to n in the tube. n is the speed at which a small
disturbance travels in a compliant tube filled with gas. The
maximal flow in a compliant tube (V’max) is the product of
velocity and tube area [19]. Thus, far,1, velocity and V’max are
related. These considerations can, however, only be qualitative
and not quantitative, since the relationship between far,1,
airway path length, airway wall compliance and the frequency
of the travelling pressure waves is highly nonlinear [26, 30, 36–
40]. Nevertheless, based on these findings, the present authors
hypothesise that the ability of airways to carry large flows is
very different in pre-term than in full-term infants.
EUROPEAN RESPIRATORY JOURNAL
M. HENSCHEN ET AL.
Limitations to the study and concomitant factors
The main limitation of the current study was the fact that
measurements were made through a face mask, and the
smaller the child, the larger the contribution of the shunt
compliance of the face mask [30]. The present authors tried to
overcome or at least partially compensate for this potential
error by using the same face mask and filling it with silicon
putty to reduce the dead space, but this could have contributed
to the lower values of far,1 among the pre-term infants since the
‘‘effective’’ dead space would have been relatively large in
relation to body size in this group. Similarly, input impedance
measurements include the upper airways, and their influence
cannot be distinguished from the lower airways [25, 29, 40]. On
the other hand, study design was strengthened by the fact that
measurements were undertaken during spontaneous unsedated sleep, thereby reflecting the complexities of the real
dynamic situation.
The lower post-conceptional age of the pre-term infants at time
of study was due both to shortened gestation and the fact that,
for practical reasons, they were measured at an earlier postnatal age than their full-term counterparts. Differences in postnatal age could, therefore, have contributed to developmental
differences of far,1 between full- and pre-term infants. While a
much larger, preferably longitudinally studied population
would be required to investigate the separate effects of
gestational versus post-natal immaturity, it should be noted
that since the pre-term infants were studied before the
expected date of delivery, the effects of pre-term birth per se
are likely to have made an important contribution. A further
potential limiting factor was the difference in ethnic background between the London and Bern groups, which partly
reflected local population characteristics, but was greater than
had been anticipated when planning the current study. In
retrospect, given the characteristics of the Swiss population,
data collection in London should have been limited to pre-term
infants born to White mothers to avoid any confounding. In
reality, given the available resources and the prolonged period
EUROPEAN RESPIRATORY JOURNAL
of recruitment this would have entailed, this was not feasible.
It has been shown that forced expiratory flows are higher in
black than white pre-term infants during the first weeks of life
[44, 45]. While such differences could reflect differences in
intrathoracic airway calibre, they are more likely to reflect
transient differences in breathing pattern during the neonatal
period among black babies, in whom a lower nasal resistance
[17, 46] and increased expiratory braking during tidal breathing [44, 45] has also been noted. While statistical analysis of the
effect of ethnicity in this study was precluded both by the
sample size and by the heterogeneity of the pre-term group
(with almost half the infants being of mixed ethnic origin
(table 1)), visual inspection of the data revealed complete
overlap according to ethnicity.
In the current study, there was also an unexpected preponderance of males, but as the proportion was similar between the
two groups, this should not have introduced any bias (fig. 2).
Numerous studies have shown that after correction for body
size, the sex of an infant has a marked effect on airway
function, though not on lung volumes, with lower maximal
expiratory flows at low lung volumes being observed in males
compared with females at any given height during infancy [45,
47–49] and later childhood. To date, nothing is known about
the influence of factors such as ethnic background, sex or body
size on high frequency Z(f) measurements, and a very large
population study (,200 infants) would probably be required
to determine such effects [50].
A further concomitant factor may be tobacco exposure. ELLIOT
et al. [51] suggested that airway wall mechanics and airway
tissue coupling is altered in tobacco-exposed newborn animals.
Therefore, it is likely that airway wall mechanics and, thus, far,1
could be altered in tobacco-exposed infants. The current study
was not sufficiently powerful to undertake subgroup analysis,
and specific details regarding prior environmental tobacco
smoke exposure were not recorded, although all the pre-term
infants were studied in hospital and thus prior to any postnatal exposures.
Conclusions and clinical implications of findings
The HIT is applicable in unsedated pre-term infants. In
common with other infant lung function tests, the far,1 has a
500
s
400
far,1 Hz
Repeatability of far,1
Despite the consistency of measurements within any one
testing session, the within-subject variability of far,1 when
measurements were repeated after several hours limits the
potential clinical usefulness of this technique. The reasons for
such variability are manifold, but include the fact that airway
wall compliance is part of a complex regulatory system
maintaining balanced flow through the airways. Other parts
of this regulatory system may be lung volume, elastic recoil
and airway diameter. The degree of between-occasion variability observed in the pre-term infants in this study is similar to
that published previously in 10 healthy unsedated full-term
infants on two different days within the same week [30]. There
are very limited data describing between-occasion repeatability for lung function tests in infants with which to compare the
current results. Due to the difficulties in undertaking such
studies, most are based on very small numbers of subjects and
all have used different approaches to reporting ‘‘repeatability’’
[41–43], which complicates comparisons. Nevertheless, most
appear to reflect a similar degree of between-occasion
variability for forced expiratory flows in infancy, as was found
for high frequency input impedance in the current study.
AIRWAY MECHANICS IN PRE-TERM INFANTS
s
l
300
l
s
s
200
s
40
FIGURE 2.
sl
l
s s
s
s
s s
l
s s
s
l
l s
s
l
s
s
l
s
s
s
s
s
s
s
s
45
50
Crown–heel length cm
55
60
Plot of far,1 against crown–heel length comparing female (#) and
male (m) infants.
VOLUME 27 NUMBER 5
917
c
AIRWAY MECHANICS IN PRE-TERM INFANTS
M. HENSCHEN ET AL.
good short-term variability within a single test occasion, but
shows considerable within-subject variation when tests are
repeated some hours later. Despite the presence of shorter
airways, the far,1 of the high frequency impedance spectrum
was significantly lower in pre-term than in full-term infants,
suggesting that differences in far,1 probably reflect differences
in n in the airways of pre-term infants when compared with
full-term infants. Due to the complex nature of wave physics in
compliant tubes and the limits of the study, it was not possible
to quantitatively separate the impact of the different components on far,1. Based on qualitative considerations, however,
the present findings suggest that developmental differences in
airway wall mechanics and airway–parenchyma coupling
influencing airway wall compliance may play a critical role
in determining far,1. The latter would be consistent with
morphological data in published animal models, showing
higher compliance in immature airways [37].
This has important physiological, clinical and research
implications. Since flow limitation is determined by n and
airway cross-sectional area [19], the present authors hypothesise that the physical ability of the airways to carry large flows
is fundamentally different in pre-term and full-term infants,
and that this probably cannot be accounted for simply by the
absolute reduction in airway dimensions found in such infants.
Interestingly, wave propagation and mechanical properties of
the airway walls determine when the airway walls start to
resonate (wheezing), since it is then that energy is transversally
dissipated into the walls. Based on the present findings, it is
likely that these wheezing phenomena in pre-term infants
occur in a different frequency range than in older children and
adults.
Based on these findings, it is likely that flow limitation in preterm infants is not only determined by airway diameter and
airway obstruction, but additionally by the mechanical properties of the airway walls. Clinically, this means that ventilation
strategies using positive end-expiratory pressure, which affects
end-expiratory level, elastic recoil and thus airway wall
elasticity, will have a large impact on airflow through the
immature airways in these very young infants. In simple
clinical terms, if their airway walls are stabilised with
increasing end-expiratory level, this will subsequently facilitate flow through the airways. Furthermore, it implies that
flow limitation in respiratory distress with high intrathoracic
pressure during active expiration might limit the airways more
dramatically in pre-term than in healthy full-term infants.
Drugs such as bronchodilators, which not only cause airway
dilation but also increase airway wall compliance [52], may
therefore reduce the flow in these collapsible immature
airways. Bronchodilators thus need to be used with care, as
they may potentially cause adverse effects in such infants [53,
54]. This study has emphasised the importance of airway wall
mechanics in pre-term infants; future studies are required to
investigate whether factors such as post-inflammatory airway
wall remodelling, sex, ethnic group, post-natal age or tobacco
exposure have additional effects on airway wall mechanics in
these immature infants.
ACKNOWLEDGEMENTS
The authors would like to thank S. Reid for help with data
collection and analysis, and G. Ihorst for statistical advice and
918
VOLUME 27 NUMBER 5
assistance. The authors would also like to thank the staff of the
Special Care Baby Unit at the Homerton Hospital, London, UK,
and the parents of all the infants who participated in this
study, for their co-operation.
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